Screening of Clinically Approved and Investigation Drugs as Potential Inhibitors of SARS‐CoV‐2: A Combinedin silicoandin vitroStudy

• DOI: 10.1002/minf.202100062
• Publication Date: 2021-09-16T12:47:03Z
• Authors: Serdar Durdagi; Muge Didem Orhan; Busecan Aksoydan; Seyma Calis; Berna Dogan; Kader Sahin; Aida Shahraki; Necla Birgül Iyison; Timucin Avsar
• Keywords: 0301 basic medicine; Ritonavir; Cefotiam; SARS-CoV-2; Drug Evaluation, Preclinical; Drug Repositioning; Drugs, Investigational; Antiviral Agents; COVID-19 Drug Treatment; 3. Good health; Molecular Docking Simulation; 03 medical and health sciences; Spike Glycoprotein, Coronavirus; Humans; Angiotensin-Converting Enzyme 2; Coronavirus 3C Proteases

AbstractIn the current study, we used 7922 FDA approved small molecule drugs as well as compounds in clinical investigation from NIH's NPC database in our drug repurposing study. SARS‐CoV‐2 main protease as well as Spike protein/ACE2 targets were used in virtual screening and top‐100 compounds from each docking simulations were considered initially in short molecular dynamics (MD) simulations and their average binding energies were calculated by MM/GBSA method. Promising hit compounds selected based on average MM/GBSA scores were then used in long MD simulations. Based on these numerical calculations following compounds were found as hit inhibitors for the SARS‐CoV‐2 main protease: Pinokalant, terlakiren, ritonavir, cefotiam, telinavir, rotigaptide, and cefpiramide. In addition, following 3 compounds were identified as inhibitors for Spike/ACE2: Denopamine, bometolol, and rotigaptide. In order to verify the predictions of in silico analyses, 4 compounds (ritonavir, rotigaptide, cefotiam, and cefpiramide) for the main protease and 2 compounds (rotigaptide and denopamine) for the Spike/ACE2 interactions were tested by in vitro experiments. While the concentration‐dependent inhibition of the ritonavir, rotigaptide, and cefotiam was observed for the main protease; denopamine was effective at the inhibition of Spike/ACE2 binding.